Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of ras oncogenes and mutant p53 to activate reporter gene expression from human and rodent mdr1 gene promoters was described, although functional significance of this finding was unclear. We analyzed the influence of various forms of recombinant human ras and p53 on the mdr1 gene expression and P-glycoprotein (Pgp) function in rodent immortalized fibroblasts. The ras genes, in addition to activation of exogenous human mdr1 gene promoter, caused an increase in (i) expression of endogenous mdr1 mRNA, (ii) Pgp activity as determined by flow cytometry analysis of Rhodamine 123 exclusion, and (iii) resistance of cells to the cytotoxic action of colchicine and some other drugs. To elucidate whether the same signalling pathway is responsible for multidrug resistance induced by various oncogenes and protein kinase C (PKC), we tested the effects of v-mos and the PKC agonist 12-O-tetradecanoylphorbol-13-acetate. Similarly to cells transformed by ras, a Rat1 subline transformed by the v-mos oncogene was characterized by decreased drug sensitivity. On the contrary, Rat1 cells treated with the protein kinase C agonist 12-O-tetradecanoylphorbol-13-acetate showed neither increased mdr1 mRNA expression nor stimulation of Pgp function. Introduction by retrovirus-mediated gene transfer of wild-type p53 into Rat1 cells or into murine p53-deficient 10(1) and 10(3) cells did not change the Pgp function significantly, whereas in Rat1 cells transformed by activated N-ras or v-mos, expression of wild-type p53 caused partial reversion of oncogene-induced drug resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Influence of exogenous ras and p53 on P-glycoprotein function in immortalized rodent fibroblasts. 852 64

Oncogenic ras genes relate to the development of human cancers. In this study, we used a plasmid-mediated short-hairpin RNA (shRNA) targeting N-ras gene to combine with clinical drug vincristine (VCR) for the treatment of human hepatoma cells. Our results showed that anti-N-Ras shRNA expression vector (pCSH1-shNR) knocked down the target mRNA and protein. Higher efficacy on growth inhibition was observed when pCSH1-shNR was combined with VCR. This synergistic effect was associated with abrogation of VCR-induced overexpressions of P-glycoprotein and multidrug resistance-associated protein 1 by pCSH1-shNR through downregulations of N-Ras and total Ras. Western blot analysis showed that pCSH1-shNR-induced downregulations of N-Ras and total Ras were potentiated by VCR. Following Ras downregulation, phosphorylations of ERK1/2 and Akt were dramatically inhibited by combinatory treatment. The data showed that pCSH1-shNR-induced inhibition of nuclear factor-kappaB was enhanced by VCR. In addition, the combination of pCSH1-shNR and VCR synergistically inhibited the growth of human hepatoma HepG2 in vivo. Our findings suggested that combination of gene-specific therapeutics and appropriate chemotherapeutic agents might be a promising approach for the treatment of human hepatocellular carcinoma.
 ...
PMID:Suppression of N-Ras by shRNA-expressing plasmid increases sensitivity of HepG2 cells to vincristine-induced growth inhibition. 1924 95

From an undifferentiated soft tissue sarcoma (STS) a cell line designated US8-93 has been established. At subcloning the cell line US8-93 three different lines (US8-93A, B and C) could be set up. In a subsequent study characteristics for ultrastructure, growth, cell cycle distribution, karyotype, protein overexpression detected by immunohistochemistry (IHC) and p53 mutational status were determined. The cell line US8-93 as well as subclones contain mainly bipolar spindle-shaped cells and additionally some polygonal and multinucleated cells. Cells possess the characteristics of primitive mesenchymal cells based on their positive reactions with anti-vimentin and negative reactions for desmin, cytokeratin, myoglobin, S100, and NSE, implying a classification as an undifferentiated STS. Cytogenetic analysis revealed nearly diploid cells with several structural and numerical aberrations for chromosomes 1, 3, 4, 6, 9, 10, 12, 13, 15 and 18. IHC positivity was found for the tumor suppressor proteins p53 and Rb, the oncogene products Bcl-2, K-ras, N-ras, P-glycoprotein Mdr-1 and MDM-2. In the p53 gene a nonsense mutation in exon 4 was detected, that was confirmed in the original primary tumor and in three derivative clonal lines. The described STS cell line represents a valuable supplementation to the relatively small number of human STS cell lines currently available and may also provide a good in vitro model for studies of STS tumorigenesis in respect to a mutated p53 gene.
 ...
PMID:Morphological and molecular characterization of an undifferentiated soft tissue sarcoma cell line and derivative clones. 2152 41